The overall goal of this proposed research is to synthesize and pre- clinically evaluate several new series of reversible and irreversibly binding cocaine antagonists in the methylphenidate class of stimulant agents. Extensive structural modifications involving the piperidine, ester moiety and aromatic ring of methylphenidate will be examined. It is anticipated that these structural modifications will provide therapeutic agents which inhibit cocaine binding, but spare dopamine uptake. The syntheses of des-benzene methylphenidate and a novel class of methylphenidate-like analogs (with piperidine ring replacement) are also proposed. These compounds will be evaluated in rats striatal tissue sin vitro for activity at the cocaine binding site using the [3H]WIN 35, 428 radioreceptor assay and for their ability to block synaptosomal [3H] dopamine transport. The ability to antagonize the behavioral effects of cocaine mediated through central dopaminergic pathways will be assessed utilizing tests which measure locomotor activity, cocaine discrimination and rotation following unilateral nigrostriatal lesions. Compounds which exhibit partial agonist or antagonist activity in the behavioral testings will be further evaluated ex vivo in the [3H]WIN 35, 428 and [3H] dopamine transport assays to obtain a better understanding of their interactions with the dopamine uptake complex in vivo. Computational modeling studies will be initiated to rationalize the biological significance of discrimination ratio (DR). Correlation between potency, dopamine uptake, DR, and the computational chemical analyses will be used to establish new structure activity relationships and hence, identify compounds which may be useful in directing efforts to develop medications for cocaine abuse. Successful completion of this research program will result in drugs with therapeutic potential against the reinforcing and addicting properties of cocaine. Ultimately, this work could serve as a significant contribution to the solution of cocaine addiction problem, a major continuing problem in the United States.